Ketones from aldehydes via alkyl C(sp3)−H functionalization under photoredox cooperative NHC/palladium catalysis

Direct synthesis of ketones from aldehydes features high atom- and step-economy. Yet, the coupling of aldehydes with unactivated alkyl C(sp3)-H remains challenging. Herein, we develop the synthesis of ketones from aldehydes via alkyl C(sp3)-H functionalization under photoredox cooperative NHC/Pd catalysis. The two-component reaction of iodomethylsilyl alkyl ether with aldehydes gave a variety of β-, γ- and δ-silyloxylketones via 1,n-HAT (n = 5, 6, 7) of silylmethyl radicals to generate secondary or tertiary alkyl radicals and following coupling with ketyl radicals from aldehydes under photoredox NHC catalysis. The three-component reaction with the addition of styrenes gave the corresponding ε-hydroxylketones via the generation of benzylic radicals by the addition of alkyl radicals to styrenes and following coupling with ketyl radicals. This work demonstrates the generation of ketyl radical and alkyl radical under the photoredox cooperative NHC/Pd catalysis, and provides two and three component reactions for the synthesis of ketones from aldehydes with alkyl C(sp3)-H functionalization. The synthetic potential of this protocol was also further illustrated by the late-stage functionalization of natural products.

Being one of the most basic functional groups with remarkable reactivity, ketones play a fundamental role in synthetic organic chemistry. In addition, they are also important and ubiquitous motifs in natural products, pharmaceuticals and functional materials [1][2][3][4] . Classic approaches to ketones include the oxidation of alcohols and acylation reaction with activated acyl electrophiles (Fig. 1a), such as acyl chlorides, amides, anhydrides and thioesters, via Friedel-Crafts acylation 5 , substitution with organometallic reagents 6,7 , and transition metalcatalyzed coupling with organostannanes, boronic esters, and halides [8][9][10] . In modern organic synthesis, direct acylation with aldehydes is an alternative and attractive approach to ketones, featuring high atom-and step-economy 11 . Most acylation reactions with aldehydes rely on transition metal (TM) catalysis (Fig. 1b). The TMcatalyzed coupling of aldehydes with organoboronic reagents [12][13][14] , hypervalent iodine reagents 15,16 and aryl/alkyl halides [17][18][19] has been well established. In addition, the TM-catalyzed aryl-H acylation with aldehydes were also reported [20][21][22][23] . Recently, the pioneering acylation of benzylic C(sp 3 )-H bonds was developed via photoredox Ni catalysis 24 . The direct acylation of unactivated alkyl C(sp 3 )-H bonds with aldehydes is one of the most appealing approaches for ketone synthesis but far less developed.
The efficient and selective functionalization of C(sp 3 )-H bond has been a long-standing challenge in organic chemistry due to the intrinsic chemical inertness and similarity in electronic and steric properties of C(sp 3 )-H bonds 51,52 . The NHC-catalyzed acylation of C(sp 3 )-H bonds has broad potential application in ketone synthesis with reductive in the number of the synthetic steps, but is not well developed. The primary progress has been achieved in the acylation of activated benzylic and α-amino C(sp 3 )-H bonds by Rovis 53 , Studer 54 , Wang 55 , and Ohmiya groups 56 . In contrast, the NHC-catalyzed acylation of ubiquitous unactivated alkyl C(sp 3 )-H bonds remains a considerable challenge 57 . Very recently, Li and co-workers reported NHC-catalyzed remote C(sp 3 )-H acylation of benzylic and unactivated alkyl C(sp 3 )-H bonds (only two special examples) of amides through N-centered radical-mediated 1,5-hydrogen atom transfer (HAT) mechanism 58 .
In this work, we report the photoredox cooperative NHC/Pd-catalyzed synthesis of ketones via two and three-component reactions with alkyl C(sp 3 )-H functionalization (Fig. 1d). This process involves palladium-triggered primary carbon-centered radical-mediated 1,n-HAT to activate remote C(sp 3 )-H bonds [59][60][61] and the following coupling of the resultant radicals 62 . This reaction features mild reaction conditions and broad functional group tolerance. The potential application of this methodology is further illustrated by the late-stage acylation of the natural products.

Condition optimization of two-component reaction
The two-component model reaction of iodomethylsilyl ether of aliphatic alcohol 1a and picolinaldehyde 2a was investigated under photoredox NHC/Pd catalysis (Table 1). We were encouraged that the  reaction gave the desired acylation product 3a after 1,6-HAT in 24% yield with similar amount of undesired direct coupling product 4a and other byproducts 59 via dehydrogenation, when carried out in the presence of 20 mol% of thioazolium preNHC N1, 10 mol% of Pd(OAc) 2 , 20 mol% of bidentate diphenyl-Xantphos L1 with 2.0 equivalent Cs 2 CO 3 in trifluorotoluene under blue LED irradiation (entry 1). Screening of preNHCs found that the preNHC N2 with free hydroxyl group performed better to give ketone 3a in 37% yield without 4a (entry 2). When the preNHC N3 with hydroxyl protected was used instead of N2, the yield of 3a decreased and with the formation of 4a (entry 3). Screening of ligands revealed that the reaction using dicyclohexyl-Xantphos L2 instead of diphenyl L1 gave the desired product 3a in some decreased yield but without 4a (entry 4). Thus, the monodentate tricyclohexylphosphine was then employed, resulting in dramatical improvement of the yield of 3a without 4a (entry 5). Other palladium source, such as Pd(PPh 3 ) 4 , Pd(TFA) 2 , and PdCl 2 is inferior to Pd(OAc) 2 (entries 6-8). Decreasing the loading of preNHC, Pd, or ligand resulted in decreased yields (entries 9-11). The yield of 3a was decreased to 29% under white LEDs irradiation (entry 12). Control experiments revealed all of preNHC, Pd and photoirradiation are crucial for the reaction (entries 13-15).

Substrate scope of two-component reaction
With the optimized reaction conditions in hand, the substrate scope of aldehyde was then explored (Figs. 2 and 3a-ah). Picolinaldehyde with 3-chloro resulted in decreased yield (3b), possible due to difficulty of the formation of Breslow intermediate stemming from the hindrance of the chloro substituent. The reaction of picolinaldehyde with different substituents, such as Me, OMe and Cl, at 4 or 5-position, all reacted smoothly to give ketones (3c-3g) in moderate to good yields. 6-Methyl substituent on picolinaldehyde resulted in low yield (3h), possibly owing to the increasing steric hindrance. Alkynyl substituent was well tolerated, giving ketone 3i in 90% yield. The picolinaldehydes with a range of additional substituted aryl group (Ar' = 4-MeOC 6 H 4, 4-CNC 6 H 4 , 3,5-(CF 3 ) 2 C 6 H 3 ), heteroaryl group (Ar' = 2-thienyl) and fused aryl group (Ar' = 1-naphthyl, 9-anthranyl, 9-phenanthryl), all worked well, providing the corresponding products 3j-3q in moderate to good yields. Isoquinoline-3-carbaldehyde performed much better than quinoline-2-carbaldehyde (3r vs. 3s), possibly due to the increasing steric hindrance. Pyrazine-2-carbaldehyde afforded the desired product (3t) in 47% yield. The reaction of thiazole-2-carbaldehydes furnished the corresponding products 3u-3v in decreased yields. Unexpectedly, benzaldehyde did not work under the same conditions as picolinaldehyde. Considering the possible coordination of palladium with picolinaldehyde, 2-hydroxypyridine derivatives were added as additive for the reaction of benzaldehyde (see Supplementary Table 3). We were pleased to find that the reaction of benzaldehyde with aliphatic silyl ether 1a afforded multifunctionalized tetrahydrofuran 3w' in 61% yield after desilylation, when 20 mol% of 2-hydroxy-5-trifluoromethylpyridine was added as the additive. The corresponding reaction with γ-phenyl silyl ether proceeded smoothly to produce 3x in 72% yield with acylation of benzylic C(sp 3 )-H bond. The scope with respect to benzaldehyde was evaluated. Benzaldehydes bearing electron-donating (X = 4-Me) or electron-withdrawing groups (X = 4-F, 4-Cl, 4-Br, 4-CF 3 , 4-CO 2 Me, 4-CN) on the para-position all worked well to give the corresponding ketones 3y-3ae in moderate to good yields. The benzaldehydes with metaor ortho-substituent (3-Cl, 2-CN) were also tolerated affording the products 3af and 3ag in 48% and 88% yield, respectively. In addition, cinnamyl aldehyde was also compatible to produce the α,β-unsaturated ketone 3ah albeit with decreased yield. However, simple aliphatic aldehydes did not work for the reaction under the current reaction conditions. Silyl ether derived from varied alcohol was then examined (Figs. 2 and 3ai-az). Primary alcohols, such as 3-methylbutan-1-ol and 2-cyclohexylethan-1-ol, furnished the desired ketones 3ai and 3aj in good yields. It was noteworthy that the reaction of non-symmetric secondary alcohol bearing two tertiary C(sp 3 )-H gave the ketone 3ak with exclusive γ-regioselectivity via 1,6-HAT. The terminal chloro in secondary alcohol was tolerated, affording the ketone 3al in 67% yield. Interestingly, hexan-2-ol and cyclooctanol derived ether without tertiary C(sp 3 )-H could also participate in the reaction with exclusive γregioselectivity at secondary C(sp 3

)-H albeit in low yields (3am & 3an).
Beyond the favored 1,6-HAT, the reaction of alkyl ether with βand δtertiary C(sp 3 )-H gave the corresponding ketones 3ao and 3ap in acceptable yields via 1,5-and 1,7-HAT, respectively. 4-Arylbutan-2-ols bearing different substituents (X = 4-H, 4-OMe, 4-NMe 2 , 4-Br, 2-Br) all worked well to give the corresponding ketones 3aq-3au in moderate to good yields. The reaction of iodomethylsilyl ether of 1phenylpropan-2-ol afforded the corresponding product 3av via 1,5-HAT in 94% yield. The silyl ether with γ-benzyloxyl worked for the reaction, giving the corresponding product 3aw with C-H acylation at the alpha-position of the benzyloxy in 76% yield. In addition, ester was tolerated to deliver the corresponding product 3ax in 63% yield. Importantly, cholesterol and dehydroepiandrosterone worked well for the reaction, yielding the corresponding ketones 3ay and 3az in good yields, which showed potential application of this methodology in latestage functionalization.

Substrate scope of three-component reaction
The carboacylation of alkenes provide easy access to ketones. Recently, a variety of groups have developed TM-catalyzed intramolecular 63,64 or intermolecular carboacylation [65][66][67][68] with acyl electrophiles. The NHC-catalyzed carboacylation of alkenes using aldehydes was also reported 57,62 . However, these reactions require active alkylation reagents as radical precursor. Following the twocomponent photoredox NHC/Pd-catalyzed C(sp 3 )-H acylation reaction, we then tested the corresponding three-component reaction with the addition of styrenes (Fig. 3). We were happy to find that the three-component reaction went smoothly under same conditions as the two-component reaction, and the corresponding εhydroxylketones 6 were obtained in good to high yields via alkylacylation of styrenes and following desilylation with tetrabutylammonium fluoride (TBAF).
A variety of styrenes were then tested for the reaction. It is worth noting that all styrenes with both electron-donating (X = OMe, t Bu) and electron-withdrawing (X = F, Cl, Br, CN, CF 3 ) groups at the para-position worked well, leading to ε-hydroxyl 6r-6x in good yields. Substituents at the meta-, ortho-position were tolerated to afford the products 6y-6z in high yields. The reaction of 2-vinylnaphthalene gave ketone 6aa in 69% yield. The reaction with 2-vinylpyridine or 4-vinylpyridine produced ketones 6ab and 6ac in good yields. Notably, the reaction of 1,1-diphenyl-buta-1,3-diene with conjugated C=C bonds showed exclusive regioselectivity (6ad), giving only the 1,2-alkylacylation of the terminal C=C bond in 98% yield. ω-Chlorine of the alkyl silyl ether was tolerated for the reaction, giving the ketone 6ae in 58% yield. In addition, the reaction of menthol derived silyl ether gave the corresponding product 6af with exclusive regioselectivity at the tertiary carbon of the isopropyl group even in the presence of two other tertiary C(sp 3 )-H. However, the reaction with internal or aliphatic olefins gave no desired ketone products under current conditions.
To verify the practicality of this protocol, gram-scale experiments and further chemical transformations of the products were carried out (Fig. 4). The reaction of alkyl silyl ether 7a from alcohol 7 (1.07 g, 6 mmol) with picolinaldehyde via γ-C(sp 3 )-H acylation under the standard conditions gave the silyl ether of chloroketone 3z,    which was desilylated to give hemiketal 8 (1.01 g, 59% overall yield from 7) of the corresponding γ-hydroxyl ketone. Reduction of hemiketal 8 with LiAlH 4 gave the corresponding 1,4-diol 9 in 56% yield. The reaction of ω-chlorohemiketal 8 with TMSCN afforded the corresponding silylated cyanohemiketal 10 in 55% yield. In addition, 1.12 g of ε-hydroxyl ketone 6a was also obtained from 4methylpentan-2-ol via the process of silylation, three-component coupling with styrene and picolinaldehyde, and desilylation (60% overall yield from alcohol). Dess-Martin oxidation of ε-hydroxyl ketone 6a delivered diketone 11 in 79% yield.

Mechanistic studies
A series of control experiments were carried out, in order to investigate the mechanism of this reaction. No acylation product 3a was detected when PhSeSePh was added as a radical scavenger, while the adduct 12 from the alkyl radical and PhSeSePh was detected by HRMS and isolated in 43% yield (Fig. 5a). These results indicated that the existence of primary alkyl radical via dehalogenation of the iodomethylsilyl ether. Crossover experiment with (iodomethyl)trimethylsilane as radical precursor and silyl ether 1a' without the iodomethyl substituent as proton source of possible intermolecular HAT was carried out, which resulted in no formation of ketone 14 via intermolecular HAT but ketone 13 in 73% yield without the participation of silyl ether 1a' (fully recovered) (Fig. 5b). This result rules out the intermolecular HAT pathway and suggests the formation of tertiary/secondary alkyl radical from primary alkyl radical via the intramolecular 1,n-HAT for the titled reaction. In addition, the reaction could not be fully inhibited by the addition of D 2 O or MeOH to trap the possible carbon cation or anion (Fig. 5c), which support the radical coupling pathway instead of radical/polar crossover pathway for the reaction. The light on/off experiments revealed that blue light was essential for this reaction and the chain reaction process was   excluded (see Supplementary Fig. 1). The UV−visible absorption spectra of the starting materials and catalysts were measured (see Supplementary Fig. 2). It was found that no apparent absorption for the alkyl silyl ether 1a, styrene 5a, picolinaldehyde 2a, carbene N2, phosphine ligand PCy 3 observed. There is weak absorption for Pd(OAc) 2 , which could be dramatically enhanced by the addition of phosphine ligand and/or NHC. These results suggest that Pd species worked as photocatalysts. Based on the mechanistic experiments and previous works 59,62 , the plausible catalytic cycle of this reaction was shown in Fig. 6. The Pd(0)L complex undergoes excitation by blue light to form the active [Pd(0)L]* catalyst. The single electron transfer (SET) between the [Pd(0)L]* catalyst and iodomethylsilyl ether 1 generates Pd(I) complex and methyl radical I with the leaving of iodide. The following intramolecular 1,n-HAT (n = 5, 6, 7) of methyl radical I produces secondary/tertiary radical species II. Meanwhile, the Breslow intermediate anion III, generated from aldehyde 2 under NHC catalysis, is single electron oxidized by Pd(I) complex to afford persistent ketyl radical IV and regenerates Pd(0)L catalyst. The coupling of persistent ketyl radical IV and transient alkyl radical II gives the adduct V of the two-component reaction, which is fragmented to afford the C(sp 3 )-H acylation product 3 and release NHC catalyst (two-component reaction).
When styrene 5 is added, the addition of alkyl radical II to styrene 5 affords more stable benzylic radical VI, which is then coupled with ketyl radical IV to furnish the three-component adduct VII. The fragmentation of adduct VII gives the alkylacylation product 6' and regenerates NHC catalyst (three-component reaction).
In summary, this work demonstrates the generation of ketyl radical and alkyl radical under the photoredox cooperative NHC/Pd catalysis, and provides two and three-component reactions for the synthesis of ketones via unactivated alkyl C(sp 3 )-H functionalization with aldehydes as the acylation reagents. The two-component reaction of iodomethylsilyl alkyl ether with aldehydes gave a variety β-, γand δ-silyloxylketones via 1,n-HAT (n = 5, 6, 7) of silylmethyl radicals to generate secondary or tertiary alkyl radicals and following coupling with ketyl radical from aldehydes under photoredox NHC catalysis. The three-component reaction with the addition of styrenes gave the corresponding ε-hydroxylketones via the generation of benzylic radical by the addition of alkyl radical to styrenes and following coupling with ketyl radical. Further investigation on photoredox cooperative NHC/TM catalysis is underway in our laboratory.

Methods
General procedure for two-component reaction A 5 mL vial equipped with a stir bar was charged with N2 (0.06 mmol), Pd(OAc) 2 (0.03 mmol), PCy 3 (0.06 mmol), additive (0.06 mmol for benzaldehydes and enals) and 2.0 mL of PhCF 3 . After stirring for 30 min in glove box, to the solution was added Cs 2 CO 3 (0.6 mmol), aldehydes 2 (0.45 mmol), alkyl silyl ethers 1 (0.3 mmol), and 1.0 mL of PhCF 3 . The reaction mixture was removed from the glove box and stirred under 36 W blue LED lights at room temperature for 16 h. The solution was concentrated under reduced pressure, and purified by column chromatography on silica gel to afford the desired ketones 3.

Data availability
The authors declare that the data supporting the findings of this study are available within the article and its Supplementary Information  Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/ licenses/by/4.0/.